Symptoms of many autoimmune disease are developed as a result of an abnormal immune response which proliferates and activates lymphocytic cells to erroneously recognize the own organism, and attack a certain tissue or the entire body of the own organism. The cause varies and has not been revealed yet. Heretofore, aiming at a drug for suppressing the proliferation and activation of lymphocytic cells, various immunosuppressants have been developed and clinically applied. However, such immunosuppressants have non-negligible adverse effects due to non-specific, cell-proliferation suppressing activity and cytotoxic action, bringing about problems.
Recently, Fingolimod (as known as FTY-720) having been approved as a drug against relapsing-remitting multiple sclerosis has attracted attention as a drug with a novel mechanism because it regulates immunity by controlling localization of lymphocytic cells without depleting the lymphocytic cells through the cell death. However, on the other hand, Fingolimod has a problem that serious adverse effects have been observed mainly on the cardiovascular system, including bradycardia and cardiac arrhythmia such as an atrioventricular block (AV block) (NPLs 1, 2).
A sphingosine-1-phosphate (hereinafter referred to as “S1P”) receptor is a G protein-coupled receptor (GPCR) present on the cell membrane, and five subtypes of the receptor have been identified (S1P1, S1P2, S1P3, S1P4, and S1P5; as known as endothelial differentiation genes EDG-1, EDG-5, EDG-3, EDG-6, and EDG-8). It is known that Fingolimod phosphorylated in vivo (FTY-p) binds to S1P1, S1P3, S1P4, and S1P5 receptors, and acts as an agonist.
Lymphocytic cells constantly circulate in circulating blood and lymphoid tissues at certain intervals. It is known that an S1P1 receptor on the lymphoid cell membrane has quite an important role when the lymphocytic cells migrate from a lymphoid tissue into circulating blood. An S1P1 receptor agonist represented by FTY-p binds mainly to an S1P1 receptor on lymphocytic cells and incorporates the S1P1 receptor into the cells, so that the S1P1 receptor on the lymphocytic cells disappears. Thereby, the lymphocytic cells are then sequestered in secondary lymphoid tissues, reducing the number of circulating lymphocytes. As a result, the S1P1 receptor agonist exhibits an excellent immunosuppressive activity (NPL 2). Meanwhile, it is believed from the studies on rodents that stimulating an S1P3 receptor expresses adverse effects on the cardiovascular system such as bradycardia (NPLs 3, 4). Hence, the studies on an S1P1 receptor agonist having a lowered action on an S1P3 receptor have been in progress.
In such circumstances, recently, a clinical test outcome has been reported regarding BAF312 (as known as Siponimod), an agonist selective for S1P1 and S1P5 receptors (NPL 5). In the report, the action of reducing the heart rate as the adverse effect and the effect of reducing the number of circulating lymphocytes as the efficacy were observed at the same dose. Hence, it has been demonstrated that removing only the action on an S1P3 receptor cannot remove the cardiotoxicity in clinical practices, and that at least a portion of the cardiotoxic action observed from Fingolimod is a toxicity due to an agonist stimulus to an S1P1 receptor.
An S1P1 receptor is coupled to a suppressive Gα protein (hereinafter referred to as “Gαi”). In the heart, Gαi activated by an agonist stimulus to the receptor, together with Gβγ, activates the G protein-coupled inwardly-rectifying potassium channel (hereinafter referred to as “GIRK channel”). Since a complex of GIRK1 and GIRK4 is expressed in the heart, this agonist stimulus is believed to cause cardiotoxicity such as AV block and heart rate reduction (NPLs 5, 6).
It is reported that S1P, which is an endogenous agonist, against an S1P receptor generally exhibits a 50% activation concentration (EC50 value), as an agonist activity, of approximately around 10 nM although slightly varying depending on the evaluation method. On the other hand, the blood concentration of S1P in a normal healthy person is several hundreds of nM, indicating that S1P is present at a concentration several ten-fold higher than the EC50 value. However, no cardiotoxicity is induced in a normal healthy person. There is another contradiction: BAF312, which exhibits a similar EC50 value, has an effective blood concentration of several tens of nM as in the case of FTY-p, but the cardiotoxicity is expressed even at such a low concentration.
As described above, the mechanism of how an S1P receptor agonist exhibits an immunosuppressive activity as the main effect and cardiotoxicity as the adverse effect has not been elucidated sufficiently yet.